The objectives of our studies are (1) to provide a coherent basis for understanding the electromagnetic properties and biochemical reactivity of cytochrome P450; (2) to elucidate mechanisms of oxidative and anaerobic reductive metabolism by cytochrome P450 (3) to identify and calculate reliable molecular indicators of reactivity for a series of drugs as oxidative and reductive substrates of P450; and (4) to use calculated indicators to predict relative metabolic product distributions and relate these to P450-induced toxicity in series of specific drugs in order to design safer analogs. All phases of this study will rely heavily on experimental results, and the metabolic studies will involve coordinated experiemntal collaborations. The normal oxidative reaction cycle of P450s is well characterized, involving four stable states of the enzyme and a fifth, transient reactive state that carries out the oxidation. The methods of quantum chemistry will be used to characterize the conformation, electronic structure, and spin distribution of the ground and excited states of proposed models for the heme unit in each of the five states of its normal oxidative metabolism cycle. The results will be used to calculate electromagnetic properties and electronic spectra, which can then be compared to experimental results. In this way, a realistic model for each of the five states of the enzyme will be obtained that is consistent with experimental behavior and that furnishes a more detailed description of the active site than can be provided by the experiments alone. Proposed mechanisms of both oxidative and anaerobic reductive metabolism will be tested by explicit modeling of reaction pathways of selected substrates to form a variety of observed metabolites. From these mechanistic studies, molecular properties of selected classes of substrates that could serve as predictors of their biochemical reactivity will be calculated and used to understand the basis of observed toxicity and to design safer analogs in selected series of drugs such as acetanilide derivatives and halogenated hydrocarbons.